Advertisement

Neutrophil Extracellular Traps Enhance Liver Inflammation and Fibrin Deposition in Fulminant Viral Hepatitis

  • Moira B. Hilscher
    Correspondence
    Correspondence Address correspondence to: Moira Hilscher, MD, Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 914 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104.
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    Search for articles by this author
Open AccessPublished:September 06, 2022DOI:https://doi.org/10.1016/j.jcmgh.2022.08.010
      Fulminant viral hepatitis remains a rare but devastating illness that may culminate in acute liver failure and the need for liver transplantation. Viral hepatitis is the most common cause of acute liver failure in developing countries, where access to liver transplantation is limited.
      • Lee W.M.
      Etiologies of acute liver failure.
      Certain populations, including immunosuppressed patients and pregnant women, are at increased risk of developing liver failure related to infection with particular viruses, including herpes simplex virus and hepatitis E virus. Given the limited access to liver transplantation in developing countries and persistent organ shortages worldwide,
      • Muhammad H.
      • Zaffar D.
      • Tehreem A.
      • Ting P.S.
      • Simsek C.
      • Turan I.
      • Alqahtani S.
      • et al.
      An update on usage of high-risk donors in liver transplantation.
      elucidating the pathophysiology of fulminant viral hepatitis is critical in devising novel therapeutics to prevent acute liver failure and avoid the need for liver transplantation. The study by Li et al
      • Li X.
      • Gao Q.
      • Wu W.
      • Hai S.
      • Hu J.
      • You J.
      • Huang D.
      • et al.
      FGL2-MCOLN3-autophagy axis-triggered neutrophil extracellular traps exacerbate liver injury in fulminant viral hepatitis.
      proposed a mechanism whereby expression of fibrinogen-like protein 2 (Fgl2) by neutrophils in the setting of fulminant viral hepatitis enhances formation of neutrophil extracellular traps through an autophagy-based mechanism. They found that neutrophil extracellular traps exacerbated fulminant viral hepatitis in a mouse model of murine hepatitis virus strain-3 infection by enhancing intrahepatic fibrin deposition and inflammation.
      Neutrophil extracellular traps comprise a framework of extracellular decondensed nuclear DNA that is expelled by a neutrophil and subsequently binds to a variety of nuclear and granular proteins, some of which have antimicrobial properties.
      • Brinkmann V.
      • Reichard U.
      • Goosmann C.
      • Fauler B.
      • Uhlemann Y.
      • Weiss D.S.
      • Weinrauch Y.
      • et al.
      Neutrophil extracellular traps kill bacteria.
      Neutrophil extracellular traps are thrombogenic structures that also contribute to immune defense by binding and neutralizing pathogens. Although other immune cells, such as T cells and natural killer cells, are implicated in the pathogenesis of viral hepatitis, the role of neutrophils and neutrophil extracellular traps in human viral hepatitis is not well established. CD8 T-cell responses have been implicated in the pathogenesis of acute liver failure owing to many hepatotrophic viruses, including hepatitis A and E.
      • Prabhu S.B.
      • Gupta P.
      • Durgapal H.
      • Rath S.
      • Gupta S.D.
      • Acharya S.K.
      • Panda S.K.
      Study of cellular immune response against hepatitis E virus (HEV).
      ,
      • Fleischer B.
      • Fleischer S.
      • Maier K.
      • Wiedmann K.H.
      • Sacher M.
      • Thaler H.
      • Vallbracht A.
      Clonal analysis of infiltrating T lymphocytes in liver tissue in viral hepatitis A.
      Similarly, lysis of infected hepatocytes mediated by the cytotoxic T-cell response is a significant driver of fulminant hepatitis B virus infection.
      • Wright T.L.
      • Mamish D.
      • Combs C.
      • Kim M.
      • Donegan E.
      • Ferrell L.
      • Lake J.
      • et al.
      Hepatitis B virus and apparent fulminant non-A, non-B hepatitis.
      Recent studies in a murine model of hepatitis B virus showed that neutrophil depletion does not impact the recruitment of cytotoxic T cells, but does ameliorate liver damage by decreasing the recruitment of antigen-nonspecific cells into the liver, which amplify and perpetuate the T-cell–mediated inflammatory response.
      • Sitia G.
      • Isogawa M.
      • Kakimi K.
      • Wieland S.F.
      • Chisari F.V.
      • Guidotti L.G.
      Depletion of neutrophils blocks the recruitment of antigen-nonspecific cells into the liver without affecting the antiviral activity of hepatitis B virus-specific cytotoxic T lymphocytes.
      Neutrophils similarly have been implicated in exacerbation of hepatitis resulting from adenoviral infection.
      • Maher J.J.
      • Scott M.K.
      • Saito J.M.
      • Burton M.C.
      Adenovirus-mediated expression of cytokine-induced neutrophil chemoattractant in rat liver induces a neutrophilic hepatitis.
      ,
      • Muruve D.A.
      • Barnes M.J.
      • Stillman I.E.
      • Libermann T.A.
      Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo.
      These recent studies, in conjunction with this study by Li et al,
      • Li X.
      • Gao Q.
      • Wu W.
      • Hai S.
      • Hu J.
      • You J.
      • Huang D.
      • et al.
      FGL2-MCOLN3-autophagy axis-triggered neutrophil extracellular traps exacerbate liver injury in fulminant viral hepatitis.
      showed a multifaceted and previously overlooked role of neutrophils in the pathogenesis of fulminant viral hepatitis. Thus, neutrophils constitute a potential therapeutic target that may curtail hepatotoxicity while circumventing the T-cell–driven immune response to the virus.
      Li et al
      • Li X.
      • Gao Q.
      • Wu W.
      • Hai S.
      • Hu J.
      • You J.
      • Huang D.
      • et al.
      FGL2-MCOLN3-autophagy axis-triggered neutrophil extracellular traps exacerbate liver injury in fulminant viral hepatitis.
      studied a mouse model of fulminant viral hepatitis, but its applicability to human disease is unclear, in part because of the significant heterogeneity that characterizes the human viral hepatitis syndromes and pathogens. As noted earlier, recent studies have shown that neutrophil depletion decreases liver damage in a murine model of hepatitis B virus infection.
      • Wright T.L.
      • Mamish D.
      • Combs C.
      • Kim M.
      • Donegan E.
      • Ferrell L.
      • Lake J.
      • et al.
      Hepatitis B virus and apparent fulminant non-A, non-B hepatitis.
      Interestingly, Li et al
      • Li X.
      • Gao Q.
      • Wu W.
      • Hai S.
      • Hu J.
      • You J.
      • Huang D.
      • et al.
      FGL2-MCOLN3-autophagy axis-triggered neutrophil extracellular traps exacerbate liver injury in fulminant viral hepatitis.
      observed minimal change after neutrophil depletion in their murine model of fulminant viral hepatitis, which likely was owing at least in part to differences in the models of viral hepatitis used. These discrepant findings suggest a nuanced, context-specific role of neutrophils in the pathogenesis of viral hepatitis syndromes and the need for disease-specific studies of each hepatotrophic virus.
      Li et al
      • Li X.
      • Gao Q.
      • Wu W.
      • Hai S.
      • Hu J.
      • You J.
      • Huang D.
      • et al.
      FGL2-MCOLN3-autophagy axis-triggered neutrophil extracellular traps exacerbate liver injury in fulminant viral hepatitis.
      proposed that neutrophil extracellular traps enhance intrahepatic fibrin deposition, which characterizes fulminant hepatitis through Fgl2 activation. Fgl2 converts prothrombin to thrombin and thereby contributes to fibrin deposition.
      • Ding J.W.
      • Ning Q.
      • Liu M.F.
      • Lai A.
      • Leibowitz J.
      • Peltekian K.M.
      • Cole E.H.
      • et al.
      Fulminant hepatic failure in murine hepatitis virus strain 3 infection: tissue-specific expression of a novel fgl2 prothrombinase.
      Fgl2 deficiency has been shown previously to improve survival in murine models of fulminant hepatitis,
      • Marsden P.A.
      • Ning Q.
      • Fung L.S.
      • Luo X.
      • Chen Y.
      • Mendicino M.
      • Ghanekar A.
      • et al.
      The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis.
      thereby confirming the role of intrahepatic fibrin deposition in its progression. Although previous studies have focused on Fgl2 production by liver sinusoidal endothelial cells,
      • Liu J.
      • Tan Y.
      • Zhang J.
      • Zou L.
      • Deng G.
      • Xu X.
      • Wang F.
      • et al.
      C5aR, TNF-alpha, and FGL2 contribute to coagulation and complement activation in virus-induced fulminant hepatitis.
      Li et al
      • Li X.
      • Gao Q.
      • Wu W.
      • Hai S.
      • Hu J.
      • You J.
      • Huang D.
      • et al.
      FGL2-MCOLN3-autophagy axis-triggered neutrophil extracellular traps exacerbate liver injury in fulminant viral hepatitis.
      here found that Fgl2 expression by neutrophils is critical in promoting neutrophil extracellular trap formation. They collected peripheral neutrophils from patients with acute liver injury/acute liver failure resulting from hepatitis B virus infection and found a significant increase in messenger RNA levels of Fgl2, suggesting a direct impact of hepatitis B virus on neutrophil populations. Li et al
      • Li X.
      • Gao Q.
      • Wu W.
      • Hai S.
      • Hu J.
      • You J.
      • Huang D.
      • et al.
      FGL2-MCOLN3-autophagy axis-triggered neutrophil extracellular traps exacerbate liver injury in fulminant viral hepatitis.
      postulated that Fgl2-induced neutrophil extracellular trap formation also contributes to the systemic coagulopathy seen in acute liver injury/acute liver failure resulting from hepatitis B virus infection. The thrombogenic impact of neutrophil extracellular traps on the microenvironment in the liver in the setting of the systemic coagulopathy that characterizes acute liver failure is a complex and interesting dichotomy that merits further study.
      Overall, this article provides helpful big-picture insights into the role of neutrophils and neutrophil extracellular traps in promoting intrahepatic fibrin deposition, which is a known contributor to the pathogenesis of acute liver failure. We look forward to more nuanced studies that clarify the interaction of neutrophils and neutrophil extracellular traps with other immune cell populations and the role of neutrophils in the pathogenesis of individual viral hepatitis syndrome.

      References

        • Lee W.M.
        Etiologies of acute liver failure.
        Semin Liver Dis. 2008; 28: 142-152
        • Muhammad H.
        • Zaffar D.
        • Tehreem A.
        • Ting P.S.
        • Simsek C.
        • Turan I.
        • Alqahtani S.
        • et al.
        An update on usage of high-risk donors in liver transplantation.
        J Clin Med. 2021; 11: 215
        • Li X.
        • Gao Q.
        • Wu W.
        • Hai S.
        • Hu J.
        • You J.
        • Huang D.
        • et al.
        FGL2-MCOLN3-autophagy axis-triggered neutrophil extracellular traps exacerbate liver injury in fulminant viral hepatitis.
        Cell Mol Gastroenterol Hepatol. 2022; (Epub ahead of print)
        • Brinkmann V.
        • Reichard U.
        • Goosmann C.
        • Fauler B.
        • Uhlemann Y.
        • Weiss D.S.
        • Weinrauch Y.
        • et al.
        Neutrophil extracellular traps kill bacteria.
        Science. 2004; 303: 1532-1535
        • Prabhu S.B.
        • Gupta P.
        • Durgapal H.
        • Rath S.
        • Gupta S.D.
        • Acharya S.K.
        • Panda S.K.
        Study of cellular immune response against hepatitis E virus (HEV).
        J Viral Hepat. 2011; 18: 587-594
        • Fleischer B.
        • Fleischer S.
        • Maier K.
        • Wiedmann K.H.
        • Sacher M.
        • Thaler H.
        • Vallbracht A.
        Clonal analysis of infiltrating T lymphocytes in liver tissue in viral hepatitis A.
        Immunology. 1990; 69: 14-19
        • Wright T.L.
        • Mamish D.
        • Combs C.
        • Kim M.
        • Donegan E.
        • Ferrell L.
        • Lake J.
        • et al.
        Hepatitis B virus and apparent fulminant non-A, non-B hepatitis.
        Lancet. 1992; 339: 952-955
        • Sitia G.
        • Isogawa M.
        • Kakimi K.
        • Wieland S.F.
        • Chisari F.V.
        • Guidotti L.G.
        Depletion of neutrophils blocks the recruitment of antigen-nonspecific cells into the liver without affecting the antiviral activity of hepatitis B virus-specific cytotoxic T lymphocytes.
        Proc Natl Acad Sci U S A. 2002; 99: 13717-13722
        • Maher J.J.
        • Scott M.K.
        • Saito J.M.
        • Burton M.C.
        Adenovirus-mediated expression of cytokine-induced neutrophil chemoattractant in rat liver induces a neutrophilic hepatitis.
        Hepatology. 1997; 25: 624-630
        • Muruve D.A.
        • Barnes M.J.
        • Stillman I.E.
        • Libermann T.A.
        Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo.
        Hum Gene Ther. 1999; 10: 965-976
        • Ding J.W.
        • Ning Q.
        • Liu M.F.
        • Lai A.
        • Leibowitz J.
        • Peltekian K.M.
        • Cole E.H.
        • et al.
        Fulminant hepatic failure in murine hepatitis virus strain 3 infection: tissue-specific expression of a novel fgl2 prothrombinase.
        J Virol. 1997; 71: 9223-9230
        • Marsden P.A.
        • Ning Q.
        • Fung L.S.
        • Luo X.
        • Chen Y.
        • Mendicino M.
        • Ghanekar A.
        • et al.
        The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis.
        J Clin Invest. 2003; 112: 58-66
        • Liu J.
        • Tan Y.
        • Zhang J.
        • Zou L.
        • Deng G.
        • Xu X.
        • Wang F.
        • et al.
        C5aR, TNF-alpha, and FGL2 contribute to coagulation and complement activation in virus-induced fulminant hepatitis.
        J Hepatol. 2015; 62: 354-362

      Linked Article